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Germline AGO2 mutations impair RNA interference and human neurological development.

Publication ,  Journal Article
Lessel, D; Zeitler, DM; Reijnders, MRF; Kazantsev, A; Hassani Nia, F; Bartholomäus, A; Martens, V; Bruckmann, A; Graus, V; McConkie-Rosell, A ...
Published in: Nat Commun
November 16, 2020

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

November 16, 2020

Volume

11

Issue

1

Start / End Page

5797

Location

England

Related Subject Headings

  • Transcriptome
  • Rats
  • RNA-Induced Silencing Complex
  • RNA, Small Interfering
  • RNA, Messenger
  • RNA Interference
  • Protein Domains
  • Phosphorylation
  • Neurons
  • Nervous System
 

Citation

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Lessel, D., Zeitler, D. M., Reijnders, M. R. F., Kazantsev, A., Hassani Nia, F., Bartholomäus, A., … Kreienkamp, H.-J. (2020). Germline AGO2 mutations impair RNA interference and human neurological development. Nat Commun, 11(1), 5797. https://doi.org/10.1038/s41467-020-19572-5
Lessel, Davor, Daniela M. Zeitler, Margot R. F. Reijnders, Andriy Kazantsev, Fatemeh Hassani Nia, Alexander Bartholomäus, Victoria Martens, et al. “Germline AGO2 mutations impair RNA interference and human neurological development.Nat Commun 11, no. 1 (November 16, 2020): 5797. https://doi.org/10.1038/s41467-020-19572-5.
Lessel D, Zeitler DM, Reijnders MRF, Kazantsev A, Hassani Nia F, Bartholomäus A, et al. Germline AGO2 mutations impair RNA interference and human neurological development. Nat Commun. 2020 Nov 16;11(1):5797.
Lessel, Davor, et al. “Germline AGO2 mutations impair RNA interference and human neurological development.Nat Commun, vol. 11, no. 1, Nov. 2020, p. 5797. Pubmed, doi:10.1038/s41467-020-19572-5.
Lessel D, Zeitler DM, Reijnders MRF, Kazantsev A, Hassani Nia F, Bartholomäus A, Martens V, Bruckmann A, Graus V, McConkie-Rosell A, McDonald M, Lozic B, Tan E-S, Gerkes E, Johannsen J, Denecke J, Telegrafi A, Zonneveld-Huijssoon E, Lemmink HH, Cham BWM, Kovacevic T, Ramsdell L, Foss K, Le Duc D, Mitter D, Syrbe S, Merkenschlager A, Sinnema M, Panis B, Lazier J, Osmond M, Hartley T, Mortreux J, Busa T, Missirian C, Prasun P, Lüttgen S, Mannucci I, Lessel I, Schob C, Kindler S, Pappas J, Rabin R, Willemsen M, Gardeitchik T, Löhner K, Rump P, Dias K-R, Evans C-A, Andrews PI, Roscioli T, Brunner HG, Chijiwa C, Lewis MES, Jamra RA, Dyment DA, Boycott KM, Stegmann APA, Kubisch C, Tan E-C, Mirzaa GM, McWalter K, Kleefstra T, Pfundt R, Ignatova Z, Meister G, Kreienkamp H-J. Germline AGO2 mutations impair RNA interference and human neurological development. Nat Commun. 2020 Nov 16;11(1):5797.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

November 16, 2020

Volume

11

Issue

1

Start / End Page

5797

Location

England

Related Subject Headings

  • Transcriptome
  • Rats
  • RNA-Induced Silencing Complex
  • RNA, Small Interfering
  • RNA, Messenger
  • RNA Interference
  • Protein Domains
  • Phosphorylation
  • Neurons
  • Nervous System